二烯丙基二硫阻断Rac1信号通路抑制结肠癌细胞EMT的分子机制

Previous studies have shown that the epithelial mesenchymal transition (EMT) is a key event in the invasion and metastasis of tumors. As an important molecule promoting development of EMT, Rac1 becomes the molecular target of the drugs curing tumor EMT, invasion, and metastasis. Diallyl disulfide (DADS), a main effective component in garlic, has significant antitumor activities. Our preliminary study found that DADS could inhibit migration and invasion of colon cancer cells, possibly related to the negative regulation of Rac1 signaling pathway. But, it is unclear whether DADS inhibits the tumor invasion and metastasis by blocking EMT mediated by the Rac1 signaling pathway. Therefore, this project aims to analyze the expression and clinical significances of the Rac1- and EMT-related molecular markers in colon cancer, analyze the effect of DADS on EMT of the colon cancer cells, analyze whether DADS inhibits EMT of colon cancer cells by blocking the Rac1 signaling pathway, and analyze whether DADS inhibits the invasion and metastasis of colon cancer xenografts in nude mice by blocking the Rac1 signaling pathway. This project can illuminate the function and mechanisms of DADS on inhibiting the invasion and metastasis mediated by EMT in colon cancer, and analyze if Rac1 is a target molecule by which DADS plays a role in the events against EMT of tumors. This project can also provide experimental evidence for development and clinical application of DADS-related novel drugs.

研究表明：上皮-间质转化 (EMT) 是肿瘤侵袭转移的关键事件，Rac1是促进EMT改变的重要分子，有望成为抗肿瘤EMT和侵袭转移药物的分子靶标。大蒜的主要有效成分二烯丙基二硫（DADS）具有较强的抗肿瘤活性。我们前期研究发现，DADS可抑制结肠癌细胞的迁移与侵袭，可能与负调控Rac1信号通路有关。但DADS是否通过阻断Rac1信号通路介导的EMT，从而抑制肿瘤侵袭转移尚不清楚。因此，项目拟分析Rac1、EMT相关分子标志在结肠癌中的表达及其临床意义；分析DADS对结肠癌细胞EMT的影响；分析DADS是否通过阻断Rac1信号通路，抑制结肠癌EMT的发生；分析DADS是否通过阻断Rac1信号通路，抑制结肠癌裸鼠移植瘤的侵袭转移。项目研究结果不仅可阐明DADS抑制结肠癌细胞EMT的作用及机制，证实Rac1是DADS发挥抗肿瘤EMT和侵袭转移的靶分子，而且能为临床开发应用DADS提供实验证据。

研究表明：上皮-间质转化 (EMT) 是肿瘤侵袭转移的关键事件，Rac1是促进EMT改变的重要分子，有望成为抗肿瘤EMT和侵袭转移药物的分子靶标。大蒜的主要有效成分二烯丙基二硫（DADS）具有较强的抗肿瘤活性。我们前期研究发现，DADS可抑制结肠癌细胞的迁移与侵袭，可能与负调控Rac1信号通路有关。但DADS是否通过阻断Rac1信号通路介导的EMT，从而抑制肿瘤侵袭转移尚不清楚。因此，我们分析了Rac1、EMT相关分子标志在结肠癌中的表达及其临床意义；分析了DADS对结肠癌细胞EMT的影响；分析了DADS通过阻断Rac1信号通路，抑制结肠癌EMT的发生。结果显示：在结肠癌中Rac1明显高表达、EMT相关分子也明显表达异常，并与临床不良预后密切相关 ；过表达Rac1在体内外可明显促进结肠癌细胞增殖、侵袭与迁移，其机制可能与其促进细胞发生EMT有关，伴随E-cadherin 表达下调，N-cadherin, vimentin, snail1表达上调；DADS可通过抑制PI3K/Akt信号通路下调Rac1的表达及其活性，从而抑制结肠癌细胞的增殖、EMT、侵袭与迁移。随后进一步发现，DADS主要通过阻断Rac1-PAK1-LIMK1-Cofilins信号通路介导的EMT来抑制结肠癌的侵袭与转移。项目研究结果提示Rac1是DADS发挥抗肿瘤EMT和侵袭转移的靶分子，可为临床开发应用DADS提供实验证据。